在多種癌癥中受體酪氨酸激酶Axl都過度表達(dá),，Axl主要在腫瘤細(xì)胞的增殖和侵襲過程中發(fā)揮作用,。
早期研究數(shù)據(jù)表明,，Axl和其配體生長阻滯特異性因子-6（GAS6）可能在建立有利于腫瘤轉(zhuǎn)移性休眠的骨髓微環(huán)境中發(fā)揮作用。目前刊登在Molecular Cancer Research雜志上的一則研究中,，研究人員發(fā)現(xiàn)轉(zhuǎn)移性前列腺癌細(xì)胞株P(guān)C3和DU145L中Axl是高表達(dá)的,，低轉(zhuǎn)移性癌細(xì)胞系LNCaP中Axl的表達(dá)水平是較低的。
敲除PC3和DU145細(xì)胞中Axl導(dǎo)致幾大間質(zhì)標(biāo)志物包括Snail,、Slug和N-鈣粘蛋白的表達(dá)降低,，而上皮標(biāo)記物E-鈣粘蛋白的表達(dá)上升，這表明Axl在前列腺上皮間質(zhì)轉(zhuǎn)化過程中發(fā)揮作用,。
敲除PC3和DU145細(xì)胞中Axl后,，腫瘤細(xì)胞的體外遷移和侵襲能力也降低。有趣的是，當(dāng)用GAS6處理PC3和DU145細(xì)胞后,，Axl蛋白水平是下降的,。
此外使用氯化鈷（缺氧誘導(dǎo)劑劑）能抑制這些細(xì)胞株GAS6介導(dǎo)Axl蛋白水平的下調(diào)。人類前列腺癌組織芯片免疫組化染色顯示,，與正常組織相比,，Axl,、GAS6和缺氧誘導(dǎo)因子-1α均表達(dá)在前列腺癌組織和骨轉(zhuǎn)移組織中,。
總之，研究表明Axl在前列腺癌轉(zhuǎn)移中起著至關(guān)重要的作用,，GAS6具有調(diào)節(jié)Axl表達(dá)的作用,。（生物谷：Bioon.com）
doi:10.1158/1541-7786.MCR-11-0569
PMC:
PMID:
Hypoxia Stabilizes GAS6/Axl Signaling in Metastatic Prostate Cancer
Anjali Mishra, Jingcheng Wang, Yusuke Shiozawa, Samantha McGee, Jinkoo Kim, Younghun Jung, et al.
The receptor tyrosine kinase Axl is overexpressed in a variety of cancers and is known to play a role in proliferation and invasion. Previous data from our laboratory indicate that Axl and its ligand growth arrest–specific 6 (GAS6) may play a role in establishing metastatic dormancy in the bone marrow microenvironment. In the current study, we found that Axl is highly expressed in metastatic prostate cancer cell lines PC3 and DU145 and has negligible levels of expression in a nonmetastatic cancer cell line LNCaP. Knockdown of Axl in PC3 and DU145 cells resulted in decreased expression of several mesenchymal markers including Snail, Slug, and N-cadherin, and enhanced expression of the epithelial marker E-cadherin, suggesting that Axl is involved in the epithelial–mesenchymal transition in prostate cancer cells. The Axl-knockdown PC3 and DU145 cells also displayed decreased in vitro migration and invasion. Interestingly, when PC3 and DU145 cells were treated with GAS6, Axl protein levels were downregulated. Moreover, CoCl2, a hypoxia mimicking agent, prevented GAS6-mediated downregulation of Axl in these cell lines. Immunochemical staining of human prostate cancer tissue microarrays showed that Axl, GAS6, and hypoxia-inducible factor-1α (Hif-1α; indicator of hypoxia) were all coexpressed in prostate cancer and in bone metastases compared with normal tissues. Together, our studies indicate that Axl plays a crucial role in prostate cancer metastasis and that GAS6 regulates the expression of Axl. Importantly, in a hypoxic tumor microenvironment Axl expression is maintained leading to enhanced signaling.
